The parasite intraerythrocytic cycle and human circadian cycle are coupled during malaria infection.

Abstract

During infections with the malaria parasites <i>Plasmodium vivax</i>, patients exhibit rhythmic fevers every 48 h. These fever cycles correspond with the time the parasites take to traverse the intraerythrocytic cycle (IEC). In other <i>Plasmodium</i> species that infect either humans or mice, the IEC is likely guided by a parasite-intrinsic clock [Rijo-Ferreira<i>et al.</i>, <i>Science</i> <b>368</b>, 746-753 (2020); Smith <i>et al</i>., <i>Science</i> <b>368</b>, 754-759 (2020)], suggesting that intrinsic clock mechanisms may be a fundamental feature of malaria parasites. Moreover, because <i>Plasmodium</i> cycle times are multiples of 24 h, the IECs may be coordinated with the host circadian clock(s). Such coordination could explain the synchronization of the parasite population in the host and enable alignment of IEC and circadian cycle phases. We utilized an ex vivo culture of whole blood from patients infected with <i>P. vivax</i> to examine the dynamics of the host circadian transcriptome and the parasite IEC transcriptome. Transcriptome dynamics revealed that the phases of the host circadian cycle and the parasite IEC are correlated across multiple patients, showing that the cycles are phase coupled. In mouse model systems, host-parasite cycle coupling appears to provide a selective advantage for the parasite. Thus, understanding how host and parasite cycles are coupled in humans could enable antimalarial therapies that disrupt this coupling.